In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after darifenacin extended-release tablets treatment. These findings are consistent with an antimuscarinic action on the urinary bladder.
The effect of a six-day treatment of 15 mg and 75 mg darifenacin extended-release tablets on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44% male, 56% female) aged 18 to 65. Subjects included 18% poor metabolizers (PMs) and 82% extensive metabolizers (EMs). The QT interval was measured over a 24-hour period both predosing and at steady-state. The 75 mg darifenacin extended-release tablets dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4 inhibitor. At the doses studied, darifenacin extended-release tablets did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7 msec when compared to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with darifenacin extended-release tablets was no different from placebo.
After oral administration of darifenacin extended-release tablets to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of darifenacin extended-release tablets 7.5 mg and 15 mg is depicted in Figure 1.
Figure 1 Mean (SD) Steady-State Darifenacin Plasma Concentration-Time Profiles for Darifenacin Extended-Release Tablets 7.5 mg and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs*
*Includes 95 EMs and 6 PMs for 7.5 mg; 104 EMs and 10 PMs for 15 mg.
A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of darifenacin extended-release tablets 7.5 mg and 15 mg in EMs and PMs of CYP2D6 is provided in Table 3.
|Darifenacin Extended-Release Tablets 7.5 mg (N = 68 EM, 5 PM)||Darifenacin Extended-Release Tablets 15 mg (N = 102 EM, 17 PM)|
|AUC24 (ng•h/mL)||Cmax (ng/mL)||Cavg (ng/mL)||Tmax (h)||t1/2 (h)||AUC24 (ng•h/mL)||Cmax (ng/mL)||Cavg (ng/mL)||Tmax (h)||t1/2 (h)|
|EM||29.24 (15.47)||2.01 (1.04)||1.22 (0.64)||6.49 (4.19)||12.43 (5.64)a||88.9 (67.87)||5.76 (4.24)||3.7 (2.83)||7.61 (5.06)||12.05 (12.37)b|
|PM||67.56 (13.13)||4.27 (0.98)||2.81 (0.55)||5.2 (1.79)||19.95c –||157.71 (77.08)||9.99 (5.09)||6.58 (3.22)||6.71 (3.58)||7.4d –|
|a N = 25; b N = 8; c N = 2; d N = 1; AUC24 = Area under the plasma concentration versus time curve for 24h;|
|Cmax = Maximum observed plasma concentration; Cavg = Average plasma concentration at steady-state;|
|Tmax = Time of occurrence of Cmax ; t1/2 = Terminal elimination half-life. Regarding EM and PM [see Clinical Pharmacology, Pharmacokinetics, Variability in Metabolism (12.3)].|
The mean oral bioavailability of darifenacin extended-release tablets in EMs at steady-state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively.
Effect of Food
Following single dose administration of darifenacin extended-release tablets with food, the AUC of darifenacin was not affected, while the Cmax was increased by 22% and Tmax was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from darifenacin extended-release tablets.
Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss ) is estimated to be 163 L.
Darifenacin is extensively metabolized by the liver following oral dosing.
Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows:
(i) monohydroxylation in the dihydrobenzofuran ring;
(ii) dihydrobenzofuran ring opening;
(iii) N-dealkylation of the pyrrolidine nitrogen.
The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of darifenacin.
Variability in Metabolism
A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM versus EM) for Cmax and AUC following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively.
Following administration of an oral dose of 14 C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the feces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13 to 19 hours.
Effects of Other Drugs on Darifenacin
Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics [see Drug Interactions (7)].
CYP3A4 Inhibitors: In a drug interaction study, when a 7.5 mg once daily dose of darifenacin extended-release tablets was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin Cmax increased to 11.2 ng/mL for EMs (n = 10) and 55.4 ng/mL for one PM subject (n = 1). Mean AUC increased to 143 and 939 ng• h/mL for EMs and for one PM subject, respectively. When a 15 mg daily dose of darifenacin extended-release tablets was given with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n = 3) and one PM subject (n = 1), respectively. Mean AUC increased to 1110 and 931 ng• h/mL for EMs and for one PM subject, respectively [see Dosage and Administration (2) and Drug Interactions (7.1)].
The mean Cmax and AUC of darifenacin following 30 mg once daily dosing at steady-state were 128% and 95% higher, respectively, in the presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, a moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at steady-state increased darifenacin Cmax and AUC by 88% and 84%, respectively [see Drug Interactions (7.1)].
The mean Cmax and AUC of darifenacin following 30 mg once daily at steady-state were 42% and 34% higher, respectively, in the presence of cimetidine, a mixed CYP P450 enzyme inhibitor.
CYP2D6 Inhibitors: Darifenacin exposure following 30 mg once daily at steady-state was 33% higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg [see Drug Interactions (7.2)].
Effects of Darifenacin on Other Drugs
In Vitro Studies: Based on in vitro human microsomal studies, darifenacin extended-release tablets are not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations.
In Vivo Studies: The potential for clinical doses of darifenacin extended-release tablets to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies.
CYP2D6 Substrates: The mean Cmax and AUC of imipramine, a CYP2D6 substrate, were increased by 57% and 70%, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean Cmax and AUC of desipramine, the active metabolite of imipramine, were increased by 260% [see Drug Interactions (7.3)].
CYP3A4 Substrates: Darifenacin (30 mg daily) co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17% increase in midazolam exposure.
Combination Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of a combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg).
Warfarin: Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state [see Drug Interactions (7.6)].
Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16% increase in digoxin exposure [see Drug Interactions (7.7)].
Pharmacokinetics in Special Populations
Age: A population pharmacokinetic analysis of patient data indicated a trend for clearance of darifenacin to decrease with age (6% per decade relative to a median age of 44). Following administration of darifenacin extended-release tablets 15 mg once daily, darifenacin exposure at steady-state was approximately 12% to 19% higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years [see Use in Specific Populations (8.5)].
Pediatric: The pharmacokinetics of darifenacin extended-release tablets has not been studied in the pediatric population [see Use in Specific Populations (8.4)].
Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady-state were approximately 57% to 79% and 61% to 73% higher in females than in males, respectively [see Use in Specific Populations (8.8)].
Renal Impairment: A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given darifenacin extended-release tablets 15 mg once daily to steady-state demonstrated no clear relationship between renal function and darifenacin clearance [see Use in Specific Populations (8.7)].
Hepatic Impairment: Darifenacin extended-release tablets pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given darifenacin extended-release tablets 15 mg once daily to steady-state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. Subjects with severe hepatic impairment (Child-Pugh C) have not been studied [see Dosage and Administration (2),Warning and Precautions (5.5) and Use in Specific Population (8.6)].
RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.